Cacchi coupling

Knochel demonstrated the effectiveness of soluble potassium or cesium alkoxides such as KO Bu or CsO Bu as well as KH in iV-methylpyrrolidinone (NMP) for promoting the 5-endo-dig cyclizations of 2-alkynylanilines to 2-substituted indoles in solution or the solid-phase <00AG(E)2488>. Alternatively, Cacchi coupled a palladium-catalyzed cyclization of o-alkynyltrifluoroacetanilides with the addition of benzyl bromide or ethyl iodoacetate to afford 2-substituted-3-benzyl or 3-indolylcarboxylate esters, respectively <00SL394>. Yamamoto reported a new palladium catalyzed indole synthesis in which 2-(l-alkynyl)-Ar-alkylideneanilines 117 give 2-substituted-3-(l-alkenyl)indoles 118 directly from the imine by the in situ coupling of an aldehyde with the alkynylaniline <00JA5662>. 

Terminal alkynes can be alkenylated by alkenyl triflates (bromides, iodides) in the presence of catalytic amounts of a palladium(O) complex (or a precursor thereof) and usually an additional substoichiometric amount of copper(I) iodide (Cul), and they can be arylated by aryl triflates (bromides, iodides). These reactions are called Cacchi coupling reactions if triflate reagents are employed, and Sonogashira-Hagihara coupling reactions if halides are used. 

Starting with 2-ethynylaniline, Cacchi and co-workers have prepared 2-aryl and 2-(cycloalkenyl)indoles by coupling followed by cyelization[7]. The reagents for the coupling step are Pd(PPh3)3. Cul Et2NH. The cyclization is... 

Cacchi and Palmier (83T3373) investigated a new entry into the quinoline skeleton by palladium-catalyzed Michael-type reactions. They found that phenyl mercurial 134 was a useful intermediate for the synthesis of quinoline derivatives, and that by selecting the reaction conditions the oxidation level of the heterocyclic ring in the quinoline skeleton can be varied. On such example is shown in Scheme 16. PdCla-catalyzed coupling between organomercurial reagent 134 and enone 135 delivered adduct 136 which was subsequently cyclized to quinoline 137 under acidic conditions. 

Heck coupling of phenyl iodide with alkenes Pd(OCOCH3)2/tris[3,5-bis(trifluoromethyl) phenyljphosphine Solvent replacement Morita et al. (1998) Cacchi et al. (1999)... 

Cacchi- and Sonogashira-Hagihara couplings occur only if a primary, secondary, or tertiary amine is present, and it is best to have the amine present in large excess. Under these conditions the acetylene will at least form a small equilibrium concentration of the corresponding ammonium acetylide or copper complex thereof. The copper iodide serves to trap this species as a copper acetylide. The copper acetylide represents a substantially improved nucleophile in comparison to the free acetylene. Without the Cul addition, the acetylide content of the reaction mixture is so small that a reaction occurs only at higher temperatures. 

Figure 16.32 represents the alkenylation of an acetylene according to the procedure developed by Cacchi. The coupling partners are an alkenyl triflate (prepared in analogy to Figure 13.23) and an alkyne. The coupling product of these compounds is a 1,3-enyne—in this case conjugated with a cyclohexenone. The C=C triple bond of such an enyne can be hydrogenated in a cis-selective fashion by using Lindlar s Pd catalyst (cf. Figure 17.81). In this way 1,3-dienes are formed that contain at least one cij-configured C=C double bond.

More often such bromo- and iodoalkynes are employed with another synthetic goal in mind, namely, in the Cadiot-Chodkiewicz reaction for the formation of symmetric or asymmetric 1,3-diynes by reaction of the haloalkyne with a terminal alkyne (Figure 13.25). Additional reagents essential for the success of this reaction are one equivalent or more of an amine and a substoichiometric amount of Cul. As with the Cacchi and Stephens-Castro coupling reactions of Section 13.3.4, a Cu-acetylide is the reactive species in the Cadiot-Chodkiewicz coupling. It is formed in step 1 of the mechanism illustrated in Figure 13.25. 

These ease of preparation of vinyl and aryl triflates and the availability of the starting materials have expanded their use as a coupling partner with a terminal acetylene. Facile Pd-Cu coupling of vinyl triflates with terminal acetylenes was reported by Cacchi [51]. The cross-coupling of enol triflate 88 with phenylacetylene proceeds easily under normal conditions [Eq. (33)] [52]. For the double cross-coupling of aromatic 1,2-ditriflates with TMSA, the addition of Bu4NI accelerates enediyne formation [Eq. (34)] [53]. 

Blaser and Spencer used aroyl halides in place of aryl halides, with aroyl chlorides being of specific interest as ubiquitous, relatively cheap compounds ( Blaser reaction ) [24], This latter reaction is normally conducted in aromatic solvents phosphines are not used here as catalyst ligands since they fully inhibit the reaction. In the same way, benzoic acid anhydrides can be used as the aryl source in combination with PdCl2 and catalytic amounts of NaBr [79]. In this reaction, one of the arenes is used in the coupling reaction by elimination of CO, whereas the other benzoate serves as the base. The benzoic acid thus formed can easily be recycled into the anhydride. The use of aryl and vinyl triflates according to Cacchi [25] and Stille [26] extends the scope of the Heck coupling to carbonyl compounds phenol derivatives act via triflate functionalization as synthetic equivalents of the aryl halides. The arylation of cyclic alkenes [27], electron-rich vinyl ethers [28], and allylic alcohols [29] is accessible through Heck reactions. Allylic alcohols yield C-C-saturated carbonyl compounds (aldehydes) for mechanistic reasons (y9-H elimination), as exemplified in eq. (6). 

Since then, many research groups have described the benefit of ionic liquids as solvents in the Mizoroki-Heck reaction covering a large variety of substrates. Cacchi et al. [22] achieved a stereoselective coupling of aryl iodides and methyl cinnamates in a mixture of molten tetrabutylammonium acetate and bromide. Intramolecular Mizoroki-Heck reactions were conducted in l- -butyl-3-methylimidazolium tetralluoroborate ([BMIm]BF4) using PdCl2 as a precatalyst. Substituted benzofurans were obtained in satisfactory yields [23]. The ionic liquid containing the palladium catalyst could be reused several times with small decrease in activity. 

The catalytic ability of dimeric palladium hydroxide in carbonylative Sonogashira coupling was demonstrated by Alper and his team in 1994 [29]. In this report, terminal alkynes and alkynols were coupled with aryl iodides in the presence of carbon monoxide in moderate to good yields (Scheme 5.6). In 1995 Cacchi and colleagues presented a general methodology for 5-(2-acylethynyl)-... 

Soler R, Cacchi S, Fabrizi Get al (2007) Sonogashira Cross-Coupling Using Carbon Aerogel Doped with Palladium Nanoparticles A Recoverable and Reusable Catalyst. Synthesis 19 3068-3072 Du H, Li B, Kang Fet al (2007) Carbon aerogel supported Pt-Ru catalysts for using as the anode of direct methanol fuel cells. Carbon 45 429-435... 

This palladium-catalyzed activation of alkynes toward nucleoplulic attack can also be adapted to oxygen nucleophiles, providing a route to benzofurans. Cacchi has demonstrated this in the Pd(OAc)2/CuISonogashira coupling/cydization of 2-halophenols with terminal alkynes (Scheme 6.8) [11]. This protocol has since... 

One of the most common examples of this approach involves the coupling of aryl or vinyl halides with palladium-catalyzed cydization. This chemistry typically employs palladium(O) catalysts, which are postulated to undergo an initial oxidative addition of aryl or vinyl halides to form a palladium(II) complex to mediate cydization. This is followed by reductive elimination of the heterocyde-aryl or heterocyde-vinyl bond. This approach has been employed to construct a range of polysubstituted indoles. For example, Cacchi has shown that the Pd(PPh3)4 catalyzed coupling of trifluoroace-tanilides with aryl halides or vinyl halides/triflates proceeds to substituted indoles in good yield (Scheme 6.14) [18]. 

As part of the chemoenzymatic synthesis of (/ )-(-)-rhododendrol, Cacchi and co-workers used perfluorotagged Pd NPs, immobilized on fluorous silica gel in the Mizoroki-Heck reaction of 4-iodophenol and 3-hydro>y-l-butene to synthesize the key intermediate 4-(4-hydro y-phenyl)butan-2-one (more commonly known as raspberiy ketone) in one step. The coupling product was further treated with the Lactobacillus brevis alcohol dehydrogenase (LMDH) in 2-propanol to give (/ )-rhodo-dendrol in 90% conversion and 99% ee (Scheme 4). 

The Heck reaction as another type of palladium-catalyzed cross-coupling reaction was also combined with a subsequent enzymatic ketone reduction. In their initial work, Cacchi et al. [64] conducted a Heck reaction of an aryhodide with butanone in organic media, and used the crude product obtained after removal of the volatile components directly for a subsequent biocatalytic reduction. The ADH turned out to be compatible with this crude product, and the desired aUyhc alcohols were obtained in yields of up to 85% and with >99% ee in all cases. 

Arcadi A, Cacchi S, Marinelli F (1989) Palladium-catalysed coupling of aryl and vinyl triflates or halides with 2-ethynylaniline an efficient route to functionalized 2-substituted indoles. Tetrahedron Lett 30 2581-2584. doi 10.1016/S0040 039(01)80456-l... 

The Heck reaction is another Pdcarbon-carbon bond forming process that is widely employed in organic synthesis and can occur in water. A recent example reported by Cacchi and coworkers was applied to the chemoenzymatic synthesis of (f ) -Rhododendrol (34) and other chiral alcohols (Scheme 4.17) (67]. To aid this work, perfluoro-tagged palladium nanoparticles (Pd p) immobilized on fluorous silica gel or through covalent bonding to silica were used as the catalytic systems. The Heck coupled product could be further treated with (R)-selective LbADH and 2-propanol to address the synthesis of (R)-Rhododendrol in 90% conversion and with 99% ee. 

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